{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T05:44:05Z","timestamp":1793339045748,"version":"4.5.0"},"reference-count":166,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:00:00Z","timestamp":1657152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The sinoatrial node (SAN) is composed of highly specialized cells that mandate the spontaneous beating of the heart through self-generation of an action potential (AP). Despite this automaticity, the SAN is under the modulation of the autonomic nervous system (ANS). In diabetes mellitus (DM), heart rate variability (HRV) manifests as a hallmark of diabetic cardiomyopathy. This is paralleled by an impaired regulation of the ANS, and by a pathological remodeling of the pacemaker structure and function. The direct effect of diabetes on the molecular signatures underscoring this pathology remains ill-defined. The recent focus on the electrical currents of the SAN in diabetes revealed a repressed firing rate of the AP and an elongation of its tracing, along with conduction abnormalities and contractile failure. These changes are blamed on the decreased expression of ion transporters and cell-cell communication ports at the SAN (i.e., HCN4, calcium and potassium channels, connexins 40, 45, and 46) which further promotes arrhythmias. Molecular analysis crystallized the RGS4 (regulator of potassium currents), mitochondrial thioredoxin-2 (reactive oxygen species; ROS scavenger), and the calcium-dependent calmodulin kinase II (CaMKII) as metabolic culprits of relaying the pathological remodeling of the SAN cells (SANCs) structure and function. A special attention is given to the oxidation of CaMKII and the generation of ROS that induce cell damage and apoptosis of diabetic SANCs. Consequently, the diabetic SAN contains a reduced number of cells with significant infiltration of fibrotic tissues that further delay the conduction of the AP between the SANCs. Failure of a genuine generation of AP and conduction of their derivative waves to the neighboring atrial myocardium may also occur as a result of the anti-diabetic regiment (both acute and\/or chronic treatments). All together, these changes pose a challenge in the field of cardiology and call for further investigations to understand the etiology of the structural\/functional remodeling of the SANCs in diabetes. Such an understanding may lead to more adequate therapies that can optimize glycemic control and improve health-related outcomes in patients with diabetes.<\/jats:p>","DOI":"10.3389\/fendo.2022.946313","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T13:43:22Z","timestamp":1657201402000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Structural and Electrical Remodeling of the Sinoatrial Node in Diabetes: New Dimensions and Perspectives"],"prefix":"10.3389","volume":"13","author":[{"given":"Lina T.","family":"Al Kury","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Chacar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman","family":"Alefishat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali A.","family":"Khraibi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moni","family":"Nader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8159.2010.02838.x","article-title":"The Anatomy and Physiology of the Sinoatrial Node\u2013a Contemporary Review","volume":"33","author":"Monfredi","year":"2010","journal-title":"Pacing Clin Electrophysiol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.616011","article-title":"New Insights into Pacemaker Activity: Promoting Understanding of Sick Sinus Syndrome","volume":"115","author":"Dobrzynski","year":"2007","journal-title":"Circulation"},{"key":"B3","article-title":"The Form and Nature of the Muscular Connections between the Primary Divisions of the Vertebrate Heart","volume":"41","author":"Keith","year":"1907","journal-title":"J Anat Physiol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2003.031542","article-title":"Sinus Node Revisited in the Era of Electroanatomical Mapping and Catheter Ablation","volume":"91","author":"Sanchez-Quintana","year":"2005","journal-title":"Heart"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.eupc.2004.03.011","article-title":"Anatomical Diversity and Age-Related Histological Changes in the Human Right Atrial Posterolateral Wall","volume":"6","author":"Matsuyama","year":"2004","journal-title":"Europace"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.209841","article-title":"Mapping Cardiac Pacemaker Circuits: Methodological Puzzles of the Sinoatrial Node Optical Mapping","volume":"106","author":"Efimov","year":"2010","journal-title":"Circ Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.206078","article-title":"Vinogradova TM. 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